2s-carboxyalkylthio-3r-imidoazetidin-4-ones and compounds useful in their preparation

ABSTRACT

2S-Carboxyalkylthio-3R-imidoazetidin-4-ones can be prepared by the sequential conversion of 2-halo-1(1&#39;&#39;-(protected)carboxy-2&#39;&#39;methylprop-1&#39;&#39;-enyl)-3R-imidoazetidin-4-ones to 2-halo-1(protected)carboxyoxalyl-3R-imidoazetidin-4-ones, which are converted to 2-halo-3R-imidoazetidin-4-ones, which are converted to 2S-(protected)carboxyalkylthio-3R-imidoazetidin-4-ones, which are converted to the title compounds. The title compounds exhibit antibacterial activity.

United States Patent [1 1 Kukolja et a1.

[ Nov. 18, 1975 both of Ind.

[73] Assignee: Eli Lilly and Company, Indianapolis,

Ind.

[22] Filed: Apr. 2, 1973 211 App]. No.: 347,276

[52] US. Cl. 260/326 S; 260/326 N; 260/239 A;

[51] Int. Cl. C07D 205/08; C07D 209/48 [58] Field of Search 260/326 N,326 S, 239 A [56] References Cited UNITED STATES PATENTS 3,487,07012/1969 Sheehan 260/326 S 3,487,071 12/1969 Sheehan 260/326 S 3,487,09012/1969 Sheehan 260/326 S 3,801,567 4/1974 I-Ieusler 260/239 A 3,842,07210/1974 Heusler 260/239 A FOREIGN PATENTS OR APPLICATIONS 2,127,2853/1971 Germany 260/239 E OTHER PUBLICATIONS Sheehan et al., J.A.C.S. 95,3064, (1973).

Goodman et al., Pharmacological Basis of Therapeutics, (1965), p. 17.

S. Wolf et al., Can. J. Chem. 50, 2894-2898, (1972).

Ibid, p. 2898-2902.

Ibid, p. 2902-2905.

Primary Examiner-Donald G. Daus Assistant ExaminerMark L. Berch 1Attorney, Agent, or FirmWilliam C. Martens, Jr.; Everet F. Smith [57]ABSTRACT 16 Claims, No. Drawings 2-halo-3R- ZS-CARBOXYALKYLTH IO-3R-IMIDOAZETIDIN- I 4-ONES AND COMPOUNDS USEFUL IN THEIR PREPARATIONBACKGROUND OF THE INVENTION om C/ i Ha COORe in which R represents acarboxy protecting group; and X represents chlorine or bromine, can beused as starting materials in the preparation of the compounds of thisinvention. 7

Compounds having the structure of Formula I can be prepared by treatmentof the corresponding 6- phthalimido penicillin ester with anelectrophilic reagent, that is, one which seeks electrons. The bondbetween the sulfur and the carbon is the 5-position of the penicillin isselectively cleaved by treatment of the penicillin with an electrophilicreagent which serves as a source of positive halogen.

The term source of positive halogen refers to a positive chlorine or apositive bromine ion. A wide variety of halogenating agents areavailable for the supply of positive halogen. Representative suitablehalogenating agents are the elemental halogens, such as chlorine andbromine, sulfuryl chloride, sulfuryl bromide, N- halogeno amides andimides, such as N-chlorosuccinimide, N-bromosuccinimide,N,N'-dibromohydantoins and organic hypohalides and particularly thealkanoyl hypohalides, such as acetyl hypochloride, propionylhypochloride, butyryl hypochloride, acetyl hypobromide, propionylhypobromide, butyryl hypobromide, and the like. Additionally, use can bemade of mixed halogens such as BrCl, ClI, Ed, and the like. The reactionof the 6-phthalimido penicillin ester and the source of positive halogenpreferably is carried out in the presence of an aprotic solvent, thatis, a solvent which does not offer or accept protons. Preferably, thereaction is carried out at a temperature within the range of from about76C. to about 80C. The mole ratio of the source of positive halogen tothe penicillin ester ranges from about 1.5:1 to about 3.021 or higher.The product (Formula I) can be isolated in accordance with readilyrecognized techniques.

SUMMARY OF THE INVENTION Broadly, this invention relates to compounds ofthe formula in which R is hydrogen or a group of the formula in which Ris a carboxy protecting group;

Z is hydrogen, chlorine, or bromine; and X is hydrogen, chlorine,bromine, or a group of the formula in which R,, and. R, independentlyare hydrogen or methyl, Y is acetamido or hydroxyl, n is zero or 1, andR is hydrogen or a carboxy protecting group readily cleavable by knowndeesterification procedures; with the limitation that one of X and Z ishydrogen, and,

' with the further limitation that, when R, is

CCOR

one of X and Z is chlorine or bromine.

Compounds useful as intermediates in accordance with this invention arethose of the formula in which R is a carboxy protecting group, and X,and Z, are hydrogen, chlorine, or bromine, with the limitation that oneof X, and Z is hydrogen.

Other compounds of this invention useful as intermediates to thepreparation of active antibiotics are those of the formula in which X,and Z, are hydrogen, chlorine, or bromine, with the limitation that oneof X, and Z, is hydrogen.

3 Further compounds of this invention, some of which are activeantibiotics and others of which are useful as intermediates in theproduction of active antibiotics are those of the formula II c H H Ra w0 fiMWM -C-(CHY) -cooRz u H o Rb DETAILED DESCRIPTION OF THE'INVENTIONCertain of the compounds of this invention can be designated 2-halo- 1protected )carboxyoxalyl-3R- phthalimidoazetidin-4-ones, and have theformula in which R is a carboxy protecting group, and X and Z arehydrogen, chlorine, or bromine, with the limitation that one of X and Zis hydrogen.

These compounds can be prepared from the corresponding compounds havingthe formula COOR in which R, X and Z are as hereinabove defined.

Compounds of Formula Ia are available in accordance with the methodhereinbefore described.

As indicated hereinabove, R designates a carboxyprotecting group, inother words, the residue of an ester-forming alcohol. Since thisinvention does not contemplate the cleavage of the ester function toproduce compounds in which R is hydrogen, the carboxyprotecting groupwhich is represented by R can be any of a wide variety of well knownfunctions. Preferably, however, R represents a group such as C to Calkyl, 2,2,2-trihaloethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl,benzhydryl, phthalimidomethyl, succinimidomethyl, phenacyl,p-halophenacyl, C to C alkanoyloxymethyl, and the like. More preferably,R is methyl, 1- butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl,benzhydryl, or 2,2,2-trichloroehtyl.

In preparing the oxalyl compounds of this invention, a compound offormula la is reacted with ozone to achieve oxidative cleavage of theinternal double bond by the formation of an ozonide intermediate.

Typically, this conversion is achieved by dissolving the compound offormula la in a suitable inert solvent. Such solvent must be one whichis itself unreactive to the highly reactive ozone. Typical suchunreactive solvents include, for example, chlorinated non-aromaticsolvents such as methylene chloride, methylene bromide, chloroform,bromoform, methyl chloride, methyl bromide, dichloroethane,dibromoethane, and the like. The compound of formula Ia, dissolved in asuitable solvent, is maintained at the temperature of reaction,typically at from about room temperature to about 76C., and preferablyat from about 10C. to about 76C. The ozone is then bubbled into thesolution maintained at the desired reaction temperature. The addition ofozone is continued until analysis of the reaction mixture indicates theabsence of any starting material. This can be determined, for example,by thinlayer chromatography (TLC) examination of a sample of thereaction mixture. Typically, the reaction will be completed within aperiod of from about 30 minutes to about 8 hours, and more generallywithin from about 1 to about 3 hours. The time of reaction, of course,will depend upon the relative amounts of reactants which are employed,the particular structure of the R group in the starting material, andthe selected reaction temperature.

Once the formation of the ozonide intermediate is complete, the ozonideas well as any excess ozone is decomposed by treatment of the reactionmixture with a reducing agent. Any of several reducing agents can beemployed, such as, for example, sodium bisulfite, sulphur dioxide,sodium iodide in acetic acid followed by sodium thiosulfate, standarddirect hydrogenation, and the like. Preferably, however, sodiumbisulfite is employed by reason of its relatively low cost andconvenience of use. The reaction mixture typically can be treated withan aqueous solution of sodium bisulfite. This treatment will accomplishthe desired decomposition of the ozonide intermediate to produce theoxalyl product. The product can be recovered from the reaction mixturein accordance with generally practiced techniques.

Typical examples of oxalyl compounds of this invention include thefollowing:

2-chlorol methoxyo xalyl-SR-phthalimidoazetidin 4-one;

2-bromol methoxyo xalyl-3R-phthalimidoazetidin- 4-one;

2-chlorol isopropylo xyoxalyl-3R-phthalimidoazetidin-4-one;

2-bromol isopropylo xyoxalyl-3R-phthalimidoazetidin-4-one;

2-chlorol t-butyloxyoxalyl-3 R-phthalimidoazetidin- 2-bromol-t-butyloxyoxalyl-3 R-phthalimidoazetidin- 4-one',

Z-chlorol -benzyloxyoxalyl-3 R-phthalimidoazetidin- 4-one', 2-bromol-benzyloxyoxalyl-3R-phthalimidoazetidin- 4-one;

2-chlorol -p-nitrobenzyloxyoxalyl-3R- phthalimidoazetidin-4-one;

Z-bromol -p-nitrobenzyloxyoxalyl-3R- phthalimidoazetidin-4-one;

2-chlorol -p-methoxybenzyloxyoxalyl-3R- phthalimidoazetidin-4-one;

Z-bromol -p-methoxybenzyloxyoxalyl-3R-.

phthalimidoazetidin-4-one;

Z-chlorol -benzhydryloxyoxalyl-3R phthalimidoazetidin-4-one;

2-bromol -benzhydryloxyoxalyl-3R- phthalimidoazetidin-4-one;

2-chlorol 2',2',2-trichloroethoxy)oxalyl-3R- phthalimidoazetidin-4-one;

2-bromol 2 ,2',2-trichloroethoxy)oxalyl-3R- phthalimidoazetidin-4-one;

Z-chloro-l -acetoxymethoxyoxalyl-3R- phthalimidoazetidin-4-one;

2-bromol -acetoxymethoxyoxalyl-3R- phthalimidoazetidin-4-one;

2-chlorol -phthalimidomethoxyoxalyl-3R- phthalimidoazetidin-4-one;

Z-bromol -succinimidomethoxyoxalyl-3R- phthalimidoazetidin-4-one;

and the like.

Haloazetidinones, preparable from the aforementioned oxalyl compounds,are also a part of this invention. These compounds are useful asintermediates in the preparation of antibiotically active compounds. Thehaloazetidinones have the following formula:

in which X and Z are hydrogen, chlorine, or bromine, with the limitationthat one of X and Z is hydrogen.

Conversion of the oxalyl compounds to their respective haloazetidinonecan be achieved by reacting the oxalyl compound with phenylhydrazine ora nitro-substituted phenylhydrazine, such as 2-nitrophenylhydrazine,4-nitrophenylhydrazine, or 2,4-dinitrophenylhydrazine.

The reaction typically is carried out by treating the oxalyl compoundwith an equivalent quantity of the phenylhydrazine reagent in anappropriate inert solvent. Any typical solvent can be employed,including, for example, ethers, such as tetrahydrofuran (THF), ethylether, dioxane, and the like, aromatic hydrocarbons such as benzene,toluene, xylene, and the like; halogenated hydrocarbons, such as, methylchloride, methyl bromide, methylene chloride, methylene bromide,chloroform, bromoform, dichloroethane, chlorobenzene, dichlorobenzene,and the like; esters, such as ethyl acetate, and the like; and variousother typical available inert solvents.

The phenylhydrazine, preferably 2,4-dinitrophenylhydrazine, is mixedwith the oxalyl compound in the selected solvent preferably in an amountequivalent ot the oxalyl compound, and the mixture is allowed to reactat a temperature from about room temperature to about 65C., preferablyfrom about 40C. to about 65C. for a period generally from about 15minutes to about 1 hour. The reaction time, of course, will depend uponthe particular reactants which are employed as well as the temperatureat which the reaction is carried out. The reaction time, thus, may varyconsiderably.

The phenylhydrazine reaction achieves cleavage of the oxalyl groupdisplacing it with a hydrogen to produce the haloazetidinone structure.The cleaved portion is removable in the form of the corresponding esterof the phenylhydrazineglyoxylate. The remaining portion of the reactionmixture contains the desired product, and the product is readilyseparable from the reaction mixture by recognized techniques, including,for example, recrystallization, preparative chromatography, and thelike.

The haloazetidinone which is formed can be either2-chloro-3R-phthalimidoazetidin-4-one or 2-bromo-3R-phthalimidoazetidin-4-one.

The 2-halo-3R-phthalimidoazetidin-4one can also be prepared by treatinga compound of the formula c @C r: *2 5 E S-C-CHO ii NH 0 CH5 withhalogen such as chlorine or bromine. The above compound, 2R-[ 1-formyl-l -(methyl)ethylthio]-3R- phthalimidoazetidin-4-one, isavailable from Sheehan et al., Journal of the American Chemical Society,87, 5468 (1965). Conversion to the Z-halo compound is quite simplyaccomplished by treating the formyl compound in an appropriate inertsolvent with a solution of the halogen which is intended to appear inthe 2-halo product. The reaction preferably can be carried out at fromabout 0C. to about 50C. and more preferably at about room temperature,and is completed in from about 15 minutes to about 4 hours.

The above-described haloazetidinones can be converted to antibioticallyactive compounds by displacement of the halogen with a protectedcarboxy-containing thio radical which is then cleaved to produce a freecarboxy substituent. The initial product produced by such displacementand containing the carboxyprotected substituent is part of the broadteaching of this invention, and the thereby-defined compounds are usefulas intermediates in the production of the antibiotically activecompounds of this invention. These ll NH Rb in which R and Rindependently are hydrogen or methyl, Y is acetamido or hydroxyl, n is Oor 1, and R is a readily removable carboxy'protecting group. By readilycleavable carboxy-protecting group is meant one which can be easilycleaved, such as by dilute aqueous base, trifluoroacetic acid,hydrogenation in the presence of a palladium or rhodium catalyst on asuitable carrier such as carbon, barium sulfate, or alumina, or byreduction with zinc in the presence of an acid such as hydrochloric,acetic, or formic acid. A variety of such carboxy protecting groups areknown for this purpose. Preferably, therefore, R represents a group suchas t-butyl, 2,2,2-trichloroethyl, benzyl, p-nitrobenzyl,p-methoxybenzyl, benzhydryl, phthalimidomethyl, phenacyl, and the like.

In achieving production of the protected-carboxy thioazetidinonecompound, the haloazetidinone is reacted with a protected-carboxymercaptan compound having the structure corresponding to the moietyintended to appear in the resulting protected-carboxy thioazetidinoneproduct.

The displacement of the halogen by the thio substituent is accomplishedby reacting the haloazetidinone with the thio moiety in the presence ofa tertiary amine base. Typical tertiary amines include, for example,triethylamine, N,N-dimethylaniline, quinoline, pyridine,N-methylmorpholine, and the like.

Typically, the selected tertiary amine'and the selected mercaptocompound are dissolved in a suitable inert solvent, such as any of thosementioned hereinabove for use in the cleavage of the oxalyl compound. Tothe mixture of the tertiary amine and the mercaptan, maintained at thetemperature of reaction, typically from about C. to about 60C., andpreferably from about C. to about 35C. (usually room temperature), thehaloazetidinone compound is added.

The reactants preferably are employed in chemically equivalent amounts,that is, a 1: 1:1 ratio of the mercaptan to the tertiary amine to thehaloazetidinone is employed. Use of excess tertiary amine is possible;however, avoidance of any excess is highly preferred. Also, it ispossible to employ an excess of the mercaptan compound; however, anyexcess must be reckoned with in isolation of the resulting product.Therefore, it is highly desirable to employ equivalent amounts of thetertiary amine and the mercaptan based upon the haloazetidinone.

The displacement reaction normally is quite rapid, being completedwithin from about 15 minutes to about 4 hours. Most often, the reactionwill be complete after about 1 hour.

The protected-carboxy thioazetidinone compound can be recovered from thereaction mixture in accordance with known techniques. Typically, thesewill include, for example, extraction, recrystallization, isolation byevaporation, chromatographic techniques, and the like.

Examples of the protected-carboxy thioazetidinones of this inventioninclude:

2S[ 1 '-(t-butyloxycarbonyl)methylthio]3R- phthalimidoazetidin-4-one;

2S[ 1 -benzyloxycarbonyl)ethylthio]-3R- phthalimidoazetidin-4-one;

2S[ 1 -(p-nitrobenzyloxycarbonyl)ethylthio]-3R-phthalimidoazetidin-4-one;

Ra 7 ,,.,..s-c-(cHY) -cooH II H o o The groups R,,, R Y, and n, aredefined as indicated hereinabove, and typical such compounds include thefollowing:

2S-(carboxymethylthio)-3R-phthalimidoazetidin- 4-one; 2S-[ 1'-(carboxy)ethylthio]-3R-phthalimidoazetidin- 4-one; 2S-[ l -(carboxy)-lmethyl)ethylthio1-3R- phthalimidoazetidin4-one; 2S-[ 1 l-(dimethyl)-2'-(acetamido)-2-(carboxy)ethylthio]3R-phthalimidoazetidin-4-one; 2S-[ 1 ,l'-(dimethyl)-2'-(hydroxy)-2'-(carboxy)ethylthio]-3R-phthalimidoazetidin-4-one; and the like. Thefree carboxy thioazetidinones of this invention have been discovered toexhibit antibiotic activity against several organisms, includingactivity against Bacillus subtilis and Serratia marcescens.

The following examples are provided to further illustrate the compoundsof this invention as well as the methods by which they are prepared.

PREPARATION 2-Chloro-3R-phthalimidol l methyoxycarbonyl-2 methylprop-l-enyl)azetidin-4-one To a solution of methyl 6-phthalimidopenicillanate(51.0 g., 142 mmol.) in 7-50 ml. of methylene chloride at C. were added,dropwise, 300 ml. of a 1 M solution of chlorine in methylene chloride.The reaction mixture was stirredfor 2 hours at 80C. Stirring wascontinued for an additional hour as the mixture warmed to roomtemperature. Evaporation of the solvent in vacuo gave, the desiredolefinic product as a white foam in an excess of yield.

EXAMPLE 1 2-Chlorol -methoxyoxalyl-3R-phthalimidoazetidin- 4-one Ozonewas passed through a solution of 2-chloro-3R- phthalimido- 1 1-methoxycarbonyl-2 '-methylprop-l enyl)-azetidin-4-one (52.0 g., 141mmol.) in 1.3 liters of methylene chloride at 20C. The reaction wasdiscontinued after about 2 hours at which time thin-layer chromatography(tlc) of a sample of the reaction mixture indicated an absence of theolefinic starting material. Sodium bisulfite (30 g.) and 20 ml. of waterwere added to the reaction mixture, and it was then vigorously stirredand allowed to warm to room temperature. After 1 hour (the reactionmixturebeing negative to a starch-iodide test), the methylene chloridesolution was decanted from the excess NaHSO The NaHSO solution waswashed with 50 ml. methylene chloride. The methylene chloride solutionswere combined and washed successively with 300 ml. NaHSO solution g. in300 ml. water), water (2 X 300 ml.), and saturated NaCl solution (400ml.). After drying over MgSO the solvent was evaporated to give 47.7grams (about 100%) of the glyoxylate product as a white foam: ir (CHCl1850 (oxalyl C=O), 1799 (B-lactam C=O), 1743 and 1778 cm (phthalimidoC=O), nmr (CHCl 240 (3,s,OCH 341 (l,d,J 2.5 Hz, B-lactam H), 374.5(l,d,J 2.5 Hz, B-lactam H) and 474 Hz (4,m,ArH).

Anal. calcd. for C14H9CIN206:

C,49.94; H, 2.69; N, 8.32; O, 28.51.

Found: C, 49.16; H, 2.88; N, 7.75; O, 28.30%.

EXAMPLE 2 2-Chloro-3R-phthalimidoazetidin-4-one A solution of2-chloro-l-methoxyoxalyl-3R- phthalimidoazetidin-4-one (24.0 g., 72mmol.) and 2,4- dinitrophenylhydrazine (14.2 g., 72 mmol.) in 650 ml. oftetrahydrofuran was refluxed for 35 minutes. The reaction mixture wascooled and evaporated to dryness. Methylene chloride (250 ml.) wasadded, the mixture was swirled to effect solution, and the red-orangemixture was then evaporated to dryness. The reaction product was thenstirred with methylene chloride (200 ml.) and filtered to give 13.4grams of methyl 2,4-dinitrophenylhydrazineglyoxylate (66%) as a lightorange amorphous solid. The filtrate was evaporated to give a lightorange foam which was chromatographed on a 5.5 cm. X 26 cm. acid-washedsilica gel column (250g. silica gel). The column was eluted with benzene(500 ml.) and then with 20% benzene-ethyl acetate, taking 24 ml.fractions every 10 minutes. Fractions 50-140 were combined andevaporated to a yellow foam which was recrystallized from CH Clpetroleum ether to give 6.3 grams of2S-chloro-3R-phthalimidoazetidin-4-one: ir (CHCl 1810 (azetidinone C=O);nmr (acetone D-6) 326 (l,d,J 1.8 Hz, azetidinone H), 368 (l,d,J 1.8 Hz,azetidinone H) and 273 Hz (4,m,ArH); mass spectrum 214 (M HCl).

Anal. calcd. for C H CIN O C, 52.71; H, 2.82; N, 11.18; 0, 19.15; Cl,14.14.

Found: C, 52.47; H, 2.72; N, 11.39; 0, 19.07; Cl, 14.14%.

A second crop of crystalline product l .3 grams) was shown by nmr to beabout a 1:1 mixture of the 2S- chloro-3R-phthalimidoazetidin-4-one andthe corresponding 2R-3R compound-Total yield was 44.5%.

EXAMPLE 3 2-Chloro-3 R-phthalimidoazetidin-4-one To a solution of 1.07g. (3 mmol.) of 2R-[1'-formyl- 1 '-(methyl)ethylthio]-3R-phthalimidoazetidin-4-one in 10 m1. of methylene chloride were added 6m1. (6 mmol.) of a 0.1 M solution of chlorine in methylene chloride.After stirring for 30 min. at room temperature, the solvent wasevaporated on a rotavapor, and the residue was dissolved in 5 ml. ofmethylene chloride. To this solution 9 ml. of petroleum ether wereadded, and, after 1 hr., 580 mg. of colorless prisms were collected; mp.l5414 155. Nmr, ir and mass spectra are virtually identical with thoseof a sample prepared from 2-chloro-1-methoxyoxalyl-3R-phthalimidoazetidin-4-one and indicate the presence of about a 9:1 ratioof 2S-chloro-3R-phthalimidoazetidin- 4-one and3R-chloro-3R-phthalimidoazetidin-4-one, respectively.

EXAMPLE 4 2S-( Benzhydryloxycarbonylmeth ylthio )-3R-phthalimidoazetidin-4-one A solution of2-chloro-3R-phthalimidoazetidin-4-one (1.0 g., 4 mmol.) in 10 ml. oftetrahydrofuran was added, dropwise, to a mixture of diphenylmethylmercaptoacetate (1.032 g., 4 mmol.) (from mercaptoacetic acid anddiphenyldiazomethane) and triethylamine (.56 ml., 4 mmol.) in 30 ml. oftetrahydrofuran at room temperature. After 30 minutes, the reactionmixture was filtered to give 530 mg. of triethylamine hydrochloride(about 100%). Evaporation of the filtrate in vacuo gave a light coloredfoam (1.87 g.) of the title compound: nmr (CHCl 209(2,s,CH S), 3l3(2,s,azetidinone H), 41 1(1,s, benzhydryl CH), 440(10,s, benzhydryl ArH), 435l,s, NH) and 465 Hz (4,m, phthalimido ArH). This product was usedwithout purification to prepare the corresponding free acid.

EXAMPLE 5 2S-( Carboxymethylthio )-3R-phthalimidoazetidin- 4-one To astirred mixture of anisole 1.3 ml.), trifluoroacetic acid (6 ml), and98100 formic acid (6 ml.) at 0C. was added2S-(benzhydryloxycarbonylmethylthio)-3R- phthalimidoazetidin-4-one (1.87g., 3.9 mmol.). After 17 minutes at 0C., the reaction mixture wasevaporated in vacuo to dryness. The crude product mixture was taken upin 25 ml. of ethyl acetate and was again evaporated to dryness. This wasrepeated three times. The crude product was then taken up in ml. ofethyl acetate, and the ethyl acetate solution was washed with water (2 X40 ml). The organic layer was then extracted with saturated sodiumbicarbonate solution (2 X 40 ml.) and water (40 ml.). The basic aqueousextracts were combined and washed with ethyl acetate" (80 ml.). Theaqueous layer was then stirred with 80 ml. of ethyl acetate, and the pHwas adjusted to 3.0 with conc. HCl. The organic layer was thenseparated, washed with brine (50 ml.), and dried over MgSO Evaporationin vacuo gave the acid as a white foam (620 mg, 52% from crude ester);nmr (acetone D- 6/CHCl 205(2,s,SCH 3l5(2,s, azetidinone H), 365(l,s,COOH) and 465 Hz (4,s,ArH); mass spectrum 306 (M 265 (M CONH) and214(M l-1SCH COOH).

EXAMPLE 6 2S[l -(Benzhydryloxycarbonyl)ethylthio]-3R-phthalimidoazetidin-4-one A solution of2-chloro-3R-phthalimidoazetidin-4-one (1.0 g., 4 mmol.) in 10 ml. oftetrahydrofuran was added, dropwise, in minutes to a mixture ofdiphenylmethyl 2-mercaptopropionate (1.12 g., 4 mmol.) and triethylamine(0.56 ml., 4 mmol.) in 40 ml. of tetrahydrofuran. After 45 minutes, thereaction mixture was filtered to give 520 mg. of triethylaminehydrochloride (about 95%). The filtrate was evaporated in vacuo to givecrude 2S-[1'-(benzhydryloxycarbonyl)ethylthio]-3R-phthalimidoaZetidin-4-one (1.77 g.), a small portion of which wasrecrystallized from CHCl /petroleum ether as a white microcrystallinesolid: ir (mull) 3385(NH) and 1785 cm (azetidinone C O); nmr* (CDCl90(3,d,J 7.6 Hz, CH 217(1,q,J 7.6 Hz,SCH), 309(2,q,J 2.4 and 3.2 Hz,azetidinone H), 334(1, m,NH), 408(1,s, benzhydryl CH), 436(s, benzhydrylArH) and 464 Hz (4,m, phthalimido ArH); mass spectrum 486(M and 443 (mCONl-l).

*Since this sample is a mixture of optical isomers, several peaks in thenmr spectrum are distorted. Anal. calcd. for C H N O S: C, 66.65; H,4.56; N. 5.76. Found: C, 66.43; H, 4.52; N, 5.83%.

EXAMPLE 7 2S-[ 1 -(Carboxy)ethylthio]-3R-phthalimidoazetidin- 4-one To astirred mixture of anisole (1 ml. trifluoroacetic acid (5 ml.), and98-100% formic acid (5 ml.) at 0C. were added 1.6 grams of2S-[1-(benzhydryloxycarbonyl)ethylthio]-3R-phthalimidoazetidin-4-one.After minutes at 0C., the reaction mixture was evaporated to dryness.The product mixture was taken up in 40 ml. of ethyl acetate and washedwith water (2 X 30 ml. The organic layer was then washed with saturatedsodium bicarbonate solution (2 X 15 ml.) and water (30 ml.). The basicaqueous extracts were combined and washed with ethyl acetate (50 ml.).The aqueous layer was then slurried with another 50 ml. of ethylacetate, and the pH was adjusted to about 3 with conc. HCl. The ethylacetate layer was then separated, washed with brine (40 ml.), and driedover MgSO Evaporation of the ethyl acetate gave the acid as a white foam(820 mg.) which was recrystallized from CHCl /petroleum ether: nmr(acetone D-6) 86 (3,d,J 7 Hz, CH 222 (1,q,J 7 Hz, SCH), 320 (2,azetidinone multiplet because sample is a mixture of optical isomers),390 (1, broad s, NH) and 472 Hz (4,m, phthalimido ArH); mass spectrum320 (M+), 277 (M CONH) and 214 [M HSCH(CH )COOH].

Anal. calcd. for C, H, N O S:

C, 52.50; H, 3.78; N, 8.75; O, 24.97; S, 10.01.

Found: C, 52.32; H, 3.88; N, 8.69; O, 25.08; S, 9.80%.

EXAMPLE 8 2S-[ 1 Benzhydryloxycarbonyl)-l-(methyl)ethylthio]-3R-phthalimidoazetidin-4-one.

To a stirred solution solution of diphenylmethyl amercaptoisobutyrate(from the acid and diphenyldiazomethane) (2.86 g., 10 mmol.) andtriethylamine (1.4 mL, 10 mmol.) in 160 ml. of tetrahydrofuran at roomtemperature was added, dropwise, a solution of2-chloro-3R-phthalimidoazetidin-4-one in 20 ml. of tetrahydrofuran.After 45 minutes, the reaction mixture was filtered and 1.35 grams oftriethylamine hydrochloride recovered. Evaporation of the filtrate gavea light colored foam. Traces of the unreacted mercapto ester wereremoved from the product by trituration with petroleum ether. Theproduct was characterized by nmr (CDCl 96 [6,s, (CH 301 (l,d,J 2.5 Hz,azetidinone H), 312 (l,d,J 2.5 Hz, azetidinone H), 368 (1,, s,NH), 403(l,s, benzhydryl CH), 436 (10,s, benzhydryl ArH) and 461 Hz (4,m,phthalimido ArH) and was used without further purification to preparethe corresponding acid.

EXAMPLE 9 2s- 1 -(Carboxy)-1 -(methyl)ethylthio]-3R- phthalimidoazetidin-4-one To a stirred solution of anisole (2 ml.),trifluoroacetic acid (8 ml.) and 98100% formic acid (2ml.) at 5C. wereadded 1.2 grams of crude 2S-[ 1 '-(benzhydryloxycarbonyl )-1 '-(methyl)ethylthio]-3R- phthalimidoazetidin-4-one. After 15 minutes, thereaction mixture was evaporated in vacuo to a viscous oil. Ethylacetacte (20 ml.) was added, and the resulting solution was againevaporated to dryness. The residue was taken up in 40 ml. of ethylacetate and washed with water (2 X 50 ml.). The organic layer was thenextracted with 5% sodium bicarbonate solution (3 X 25 ml.). Thebicarbonate extracts were combined, washed with ethyl acetate (40 ml.),and slum'ed with 40 m1. of fresh ethyl acetate, during which time the pHwas adjusted to about 2.5 with conc. HCl. The organic layer was thenseparated, washed with water (30 ml.), brine (30 ml.), and dried overMgSO The solvent was evaporated in vacuo, during which time the acidproduct precipitated from the solution. Filtration gave 280 mg. (32%) ofa white crystalline solid (mp 219222): nmr (D 0) [6,s, (CH 311 (1,d,.l 2Hz, azetidinone H), 317 (1,d,J 2 Hz, azetidinone H), and 468 Hz (4s,phthalimido ArH); ir (KBr) 1765 (azetidinone C=O), 1741 and 1775(phthalimido C=O) and 1720 cm (carboxy C=O); mass spectrum 334 (M*), 291(M CONH) and 214 [M HSC(CH COOH].

Anal. calcd. for C H N O S:

C, 53.89; H, 4.22; N, 8.38; O, 23.93; S, 9.59.

Found: C, 53.94; H, 4.50; N, 8.09; O, 24.09; S, 9.04%.

EXAMPLE 10 2S 1 ,1 -(Dimethyl)-2-(acetamido)-2-benzhydryloxycarbonyl)-ethylthio]-3R-phthalimidoazetidin-4-one.

To a solution of triethylamine (.56 ml., 4 mmol.) and diphenylmethylN-acetyl penicillamine (1.43 g., 4 mmol.) (from d1 N-acetylpenicillamine and diphenyldiazomethane) in 55 ml. tetrahydrofuran atroom temperature was added, dropwise, a solution of 2-chloro-3R-phthalimidoazetidin-4-one (1.0 g., 4 mmol.) in 15 ml.tetrahydrofuran. After 40 minutes, the reaction mixture was filtered,and the filtrate was evaporated in vacuo. The resulting crude productwas placed on a silica gel column (21 X 2.5 cm., 50 g. silica gel) andeluted successively with benzene (700 ml.), 5% benzene/ethyl acetate(1800 ml.) and 15% benzene/ethyl acetate (1000 ml.). The desired productwas eluted after about 400 ml. of the 15% benzene/ethyl acetate wasused. The azetidinone benzhydryl ester was iso- 13 lated as a lightyellow amorphous solid. The nmr of this product is consistent with thestructure, but, since it is a mixture of optical isomers (from the dlN-ace tyl peni- EXAMPLE 1 1 2S-[ 1 ',l '-(Dimethyl)-2-( acetamido )-2-(carboxy)ethylthio]-3R-phthalimidoazetidin-4-one.

To a mixture of anisole 1.2 ml.), trifluoroacetic acid (5 ml.) and98-100 formic acid (5 ml.) at 0C. were added 900 mg. of2S-[1,l-(dimethyl)-2'- (acetamido -2 benzhydryloxycarbonyl )ethylthio3R-phthalimidoazetidin-4-one. After 20 minutes at 0C., the reactionmixture was evaporated to dryness. The residue was taken up in ethylacetate (25 ml.), washed with water (2 X 20 ml.), and extracted withsodium bicarbonate solution (2 X ml.)*. The bicarbonate extracts werecombined and washed with ethyl acetate (30 ml.). The aqueous layer wasthen slurried with ml. of ethyl acetate, and the pH was adjusted to ca.2.5 with cone. HCl. The organic phase was then separated, washed withwater (20 ml.), brine (20 ml.), and dried over MgSO Evaporation of thesolvent in vacuo gave 72 mg. of a white amorphous solid identified asthe desired acid: it (CHCl 1786 azetidinone C=O), 1770 and 1730(phthalimido C=O), 1720 (carboxy C=O), and 1674 cm (acetamido C=O). Thenmr (acetone D-6) was complicated by the presence of optical isomersbut, nevertheless, agreed with the proposed structure: 78/84/86/92 [6,s,(CH 108/120 (3,s, acetamido CH 275/280/284 (l,d,J 0 Hz, CHNH), 320 (1,m,acetidinone 2-H), 322 (l ,d,J ca. 3 Hz, azetidinone 3-H), 350 (1, broads, COOH), 44 (1,d,J 9 Hz, CHNH), 471 (4, m,ArH)

and 486 Hz (1, broad s, azetidinone NH). Found: C,

53.51; H, 5.51; N, 9.97; O, 23.51; S, 7.32%. *No starting material wasfound in the 720 mg. of material isolated from the neutrals.

Anal. calcd. for C, H, N O S:

C, 53.33; H, 4.72; N, 10.36; 0, 23.68; S, 7.91.

Found: C, 53.51; H, 5.51; N, 9.97; O, 23.51; S, 7.32%.

We claim:

1. A compound of the formula in which R, is hydrogen or agroup of theformula in which R is'a carboxy protecting group; Z is hydrogemchlorine,or bromine; and X is hydrogen, chlorine, bromine, or a group of theformula in which R, and R, independently are hydrogen or methyl, Y isacetamido or hydroxyl, n is zero or 1, and R is hydrogen or a carboxyprotecting group readily cleavable by known de-esterificationprocedures; with the limitation that one of X and Z is hydrogen, and,with the further limitation that, when R, is

one of X and Z is chlorine or bromine.

2. Compound of claim 1, in which R, is hydrogen and i X or Z is chlorineor bromine.

3. Compound of claim 2, in which X is chlorine. 4. Compoundof claim 2,in which X is bromine. 5. Compound of claim 1, in which X or Z ischlorine or bromine and R, is

C OR.

p-halophenacyl.

7. Compound of claim 5, in 'which R is methyl, t-

butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, or2,2,2-trichloroethyl.

8. Compound of claim 7, in which X is chlorine.

9. Compound of claim 7 in which X is bromine.

10. Compound of claim 1, in which R, is hydrogen and X is 11. Compoundof claim 10, in which R, is a carboxy protecting group which can becleaved by dilute aqueous base, trifluoroacetic acid, hydrogenation inthe presence of a palladium or a rhodium catalyst on a suitable carrier,or reduction by zinc in the presence of an acid.

12. Compound of claim 11, in which R, is t-butyl, 2,2,2-trichloroethyl,benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, phthalimidomethyl,or phenacyl.

13. Com ound of claim 10 in which R and R are methyl, and n is Zerop 9 ab 16. Compound of claim 10, in which R and R are hydrogen and n ismethyl, n is l, and Y is acetamido. 14. Compound of dam 10, 1n WhlCll R1s hydrogen R is methyl, and n is zero. 15. Compound of claim 10, inwhich R,, and R are

1. A COMPOUND OF THE FORMULA
 2. Compound of claim 1, in which R1 ishydrogen and X or Z is chlorine or bromine.
 3. Compound of claim 2, inwhich X is chlorine.
 4. Compound of claim 2, in which X is bromine. 5.Compound of claim 1, in which X or Z is chlorine or bromine and R1 is 6.Compound of claim 5, in which R is C1 to C4 alkyl, 2,2,2-trihaloethyl,benzyl, p-nitrobenzyl, succinimidomethyl, phthalimidomethyl,p-methoxybenzyl, benzhydryl, C2 to C6 alkanoyloxymethyl, phenacyl, orp-halophenacyl.
 7. Compound of claim 5, in which R is methyl, t-butyl,benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, or2,2,2-trichloroethyl.
 8. Compound of claim 7, in which X is chlorine. 9.Compound of claim 7 in which X is bromine.
 10. Compound of claim 1, inwhich R1 is hydrogen and X is
 11. Compound of claim 10, in which R2 is acarboxy protecting group which can be cleaved by dilute aqueous base,trifluoroacetic acid, hydrogenation in the presence of a palladium or arhodium catalyst on a suitable carrier, or reduction by zinc in thepresence of an acid.
 12. Compound of claim 11, in which R2 is t-butyl,2,2,2-trichloroethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl,benzhydryl, phthalimidomethyl, or phenacyl.
 13. Compound of claim 10, inwhich Ra and Rb are hydrogen, and n is zero.
 14. Compound of claim 10,in which Ra is hydrogen, Rb is methyl, and n is zero.
 15. Compound ofclaim 10, in which Ra and Rb are methyl, and n is zero.
 16. Compound ofclaim 10, in which Ra and Rb are methyl, n is 1, and Y is acetamido.